This project aims at developing, validating and using novel mapping approaches to enhance the understanding of excitation dynamics in atrial fibrillation (AF) and to improve its treatment. AF is the most common sustained arrhythmia in humans afflicting more than 2.5 million Americans and is the leading cause of embolic stroke. For patients with AF, anti-arrhythmic drugs perform poorly and ablation, with controversial success rate and long-term effects, is often the only therapy available. Thus, advancing our understanding of the mechanisms of the arrhythmia and how to device better therapies for it are of paramount importance. It is generally accepted that fibrillation is a common end-pathway of various insults to the heart with multi-factorial alterations in the electrophysiology of the substrate and its activation patterns. It is also acceptable that the alterations promoting the onset and controlling the maintenance of fibrillation have significant regional as well as inter-patient heterogeneity. It is therefore the general objective of this proposal to develop a set of novel mapping approaches that will improve the capability of characterizing the patterns of electrical activation specific to underlying ionic heterogeneities. The proposed study will include full-view (panoramic) intracardiac optical/electrical recordings in isolated sheep hearts and electrical recordings in-vivo sheep. We will take advantage of our previous developments in fluorescence endoscopic imaging of the electrical activity of the heart and singularity value decomposition (SVD) algorithms to design and test a novel approach that in its final form will enable a better correlation between the space-time and frequency properties of the fibrillating atria, with direct possible applicability to individual patients. Our approach builds on a novel SV factorization into ranked space, time and frequency interrelated components to better localize and track potential drivers of AF. This numerical scheme will be included in 3 specific aims as follows: (i) To develop increasingly detailed computer models of the atria to simulate different AF scenarios and validate the SVD ability to point to a driver location, or whether such a driver exists. (ii) To apply the SVD approach to panoramic optical mapping data from two intact atria of isolated sheep heart. The panoramic high resolution optical mapping will be used as a reference for the SVD analysis performed on electrical intracadiac recordings. (iii) To apply the validated electrical mapping algorithms to AF in-vivo in the sheep. Reversible atrial lesions induced by cryoablation will be used to test successful localization of drivers and termination of AF. Accomplishing the aims of the study will provide a solid framework for mapping AF dynamics in patients to improve its understanding and therapy.